Quo vadis motor neuron disease?

Motor neuron disease (MND), also known as amyotrophic lateral sclerosis, is a relentlessly progressive neurodegenerative condition that is invariably fatal, usually within 3 to 5 years of diagnosis. The aetio-pathogenesis of MND remains unresolved and no effective treatments exist. The only Food and Drug Administration approved disease modifying therapy is riluzole, a glutamate antagonist, which prolongs survival by up to 3 mo. Current management is largely symptomatic/supportive. There is therefore a desperate and unmet clinical need for discovery of disease mechanisms to guide novel therapeutic strategy. In this review, we start by introducing the organizational anatomy of the motor system, before providing a clinical overview of its dysfunction specifically in MND. We then summarize insights gained from pathological, genetic and animal models and conclude by speculating on optimal strategies to drive the step change in discovery, which is so desperately needed in this arena

The mRNA expression of SATB1 and SATB2 in human breast cancer

Background SATB1 is a nuclear protein that has been recently reported to be a 'genome organizer' which delineates specific epigenetic modifications at target gene loci, directly up-regulating metastasis-associated genes while down-regulating tumor-suppressor genes. In this study, the level of mRNA expression of SATB1 and SATB2 were assessed in normal and malignant breast tissue in a cohort of women with breast cancer and correlated to conventional clinico-pathological parameters. Materials and methods Breast cancer tissues (n = 115) and normal background tissues (n = 31) were collected immediately after excision during surgery. Following RNA extraction, reverse transcription was carried out and transcript levels were determined using real-time quantitative PCR and normalized against β-actin expression. Transcript levels within the breast cancer specimens were compared to the normal background tissues and analyzed against TNM stage, nodal involvement, tumour grade and clinical outcome over a 10 year follow-up period. Results The levels of SATB1 were higher in malignant compared with normal breast tissue (p = 0.0167). SATB1 expression increased with increasing TNM stage (TNM1 vs. TNM2 p = 0.0264), increasing tumour grade (grade1 vs. grade 3 p = 0.017; grade 2 vs. grade 3 p = 0.0437; grade 1 vs. grade 2&3 p = 0.021) and Nottingham Prognostic Index (NPI) (NPI-1 vs. NPI-3 p = 0.0614; NPI-2 vs. NPI-3 p = 0.0495). Transcript levels were associated with oestrogen receptor (ER) positivity (ER(-) vs. ER(+) p = 0.046). SABT1 expression was also significantly correlated with downstream regulated genes IL-4 and MAF-1 (Pearson's correlation coefficient r = 0.21 and r = 0.162) and SATB2 (r = 0.506). After a median follow up of 10 years, there was a trend for higher SATB1 expression to be associated with shorter overall survival (OS). Higher levels of SATB2 were also found in malignant compared to background tissue (p = 0.049). SATB2 expression increased with increasing tumour grade (grade 1 vs. grade 3 p = 0.035). SATB2 was associated with ER positivity (ER(-) vs. ER(+) p = 0.0283) within ductal carcinomas. Higher transcript levels showed a significant association with poorer OS (p = 0.0433). Conclusion SATB1 mRNA expression is significantly associated with poor prognostic parameters in breast cancer, including increasing tumour grade, TNM stage and NPI. SATB2 mRNA expression is significantly associated with increasing tumour grade and poorer OS. These results are consistent with the notion that SATB1 acts as a 'master genome organizer' in human breast carcinogenesis

Stress-Specific Spatiotemporal Responses of RNA-Binding Proteins in Human Stem-Cell-Derived Motor Neurons

RNA-binding proteins (RBPs) have been shown to play a key role in the pathogenesis of a variety of neurodegenerative disorders. Amyotrophic lateral sclerosis (ALS) is an exemplar neurodegenerative disease characterised by rapid progression and relatively selective motor neuron loss. Nuclear-to-cytoplasmic mislocalisation and accumulation of RBPs have been identified as a pathological hallmark of the disease, yet the spatiotemporal responses of RBPs to different extrinsic stressors in human neurons remain incompletely understood. Here, we used healthy induced pluripotent stem cell (iPSC)-derived motor neurons to model how different types of cellular stress affect the nucleocytoplasmic localisation of key ALS-linked RBPs. We found that osmotic stress robustly induced nuclear loss of TDP-43, SPFQ, FUS, hnRNPA1 and hnRNPK, with characteristic changes in nucleocytoplasmic localisation in an RBP-dependent manner. Interestingly, we found that RBPs displayed stress-dependent characteristics, with unique responses to both heat and oxidative stress. Alongside nucleocytoplasmic protein distribution changes, we identified the formation of stress- and RBP-specific nuclear and cytoplasmic foci. Furthermore, the kinetics of nuclear relocalisation upon recovery from extrinsic stressors was also found to be both stress- and RBP-specific. Importantly, these experiments specifically highlight TDP-43 and FUS, two of the most recognised RBPs in ALS pathogenesis, as exhibiting delayed nuclear relocalisation following stress in healthy human motor neurons as compared to SFPQ, hnRNPA1 and hnRNPK. Notably, ALS-causing valosin containing protein (VCP) mutations did not disrupt the relocalisation dynamics of TDP-43 or FUS in human motor neurons following stress. An increased duration of TDP-43 and FUS within the cytoplasm after stress may render the environment more aggregation-prone, which may be poorly tolerated in the context of ALS and related neurodegenerative disorders. In summary, our study addresses stress-specific spatiotemporal responses of neurodegeneration-related RBPs in human motor neurons. The insights into the nucleocytoplasmic dynamics of RBPs provided here may be informative for future studies examining both disease mechanisms and therapeutic strategy

The translational potential of human induced pluripotent stem cells for clinical neurology: The translational potential of hiPSCs in neurology

The induced pluripotent state represents a decade-old Nobel prize-winning discovery. Human-induced pluripotent stem cells (hiPSCs) are generated by the nuclear reprogramming of any somatic cell using a variety of established but evolving methods. This approach offers medical science unparalleled experimental opportunity to model an individual patient's disease "in a dish." HiPSCs permit developmentally rationalized directed differentiation into any cell type, which express donor cell mutation(s) at pathophysiological levels and thus hold considerable potential for disease modeling, drug discovery, and potentially cell-based therapies. This review will focus on the translational potential of hiPSCs in clinical neurology and the importance of integrating this approach with complementary model systems to increase the translational yield of preclinical testing for the benefit of patients. This strategy is particularly important given the expected increase in prevalence of neurodegenerative disease, which poses a major burden to global health over the coming decades

The microglial component of amyotrophic lateral sclerosis

Microglia are the primary immune cells of the CNS, carrying out key homeostatic roles and undergoing context-dependent and temporally regulated changes in response to injury and neurodegenerative diseases. Microglia have been implicated in playing a role in amyotrophic lateral sclerosis (ALS), a neurodegenerative disease characterized by extensive motor neuron loss leading to paralysis and premature death. However, as the pathomechansims of ALS are increasingly recognized to involve a multitude of different cell types, it has been difficult to delineate the specific contribution of microglia to disease. Here, we review the literature of microglial involvement in ALS and discuss the evidence for the neurotoxic and neuroprotective pathways that have been attributed to microglia in this disease. We also discuss accumulating evidence for spatiotemporal regulation of microglial activation in this context. A deeper understanding of the role of microglia in the ‘cellular phase’ of ALS is crucial in the development of mechanistically rationalized therapies

Infiltration Characteristics of Tropical Soils at University Technology PETRONAS Campus

This study is chosen by the author is to examine the relationship between rainfall amount and settlement in University Technology Petronas (UTP), Tronoh, Perak. The settlement had occurred near student residential college, Blok K which caused a small hole on the road. The incident is said that caused by the heavy rainfall. This study is done to propose an investigation to find out the effect of rainfall to the ground settlement in UTP. This is study also to suggest the method to proceed with the investigation. From the result of this study at the end of this project, hopefully it will be useful to others in solving settlement problem and come out with other solution in order to avoid ground settlement in future. The result shows that the significant variation of soil infiltration exists in the area of studied. Larger range and the lower sill indicates that the soil infiltration are spatially dependent over long distance (large range) and the variability is low (indicates by low sill). Land disturbance and land topographic conditions contribute to the variability of soil infiltration

Decoding the relationship between ageing and amyotrophic lateral sclerosis: a cellular perspective

With an ageing population comes an inevitable increase in the prevalence of age-associated neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), a relentlessly progressive and universally fatal disease characterized by the degeneration of upper and lower motor neurons within the brain and spinal cord. Indeed, the physiological process of ageing causes a variety of molecular and cellular phenotypes. With dysfunction at the neuromuscular junction implicated as a key pathological mechanism in ALS, and each lower motor unit cell type vulnerable to its own set of age-related phenotypes, the effects of ageing might in fact prove a prerequisite to ALS, rendering the cells susceptible to disease-specific mechanisms. Moreover, we discuss evidence for overlap between age and ALS-associated hallmarks, potentially implicating cell type-specific ageing as a key contributor to this multifactorial and complex disease. With a dearth of disease-modifying therapy currently available for ALS patients and a substantial failure in bench to bedside translation of other potential therapies, the unification of research in ageing and ALS requires high fidelity models to better recapitulate age-related human disease and will ultimately yield more reliable candidate therapeutics for patients, with the aim of enhancing healthspan and life expectancy

Region-specific vulnerability in neurodegeneration: lessons from normal ageing

A number of age-associated neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD) and amyotrophic lateral sclerosis (ALS), possess a shared characteristic of region-specific neurodegeneration. However, the mechanisms which determine why particular regions within the nervous system are selectively vulnerable to neurodegeneration, whilst others remain relatively unaffected throughout disease progression, remain elusive. Here, we review how regional susceptibility to the ubiquitous physiological phenomenon of normal ageing might underlie the vulnerability of these same regions to neurodegeneration, highlighting three regions archetypally associated with AD, PD and ALS (the hippocampus, substantia nigra pars compacta and ventral spinal cord, respectively), as especially prone to age-related alterations. Placing particular emphasis on these three regions, we comprehensively explore differential regional susceptibility to nervous system tissue, cellular and molecular level ageing to provide an integrated perspective on why age-related neurodegenerative diseases exhibit region-selective vulnerability. Combining these principles with increasingly recognised differences between chronological and biological ageing (termed differential or ‘delta’ ageing) might ultimately guide therapeutic approaches for these devastating neurodegenerative diseases, for which a paucity of disease modifying and/or life promoting treatments currently exist

Obstructions to a general characterization of graph correspondences

For a countable discrete space V, every nondegenerate separable C*-correspondence over c_0(V) is isomorphic to one coming from a directed graph with vertex set V. In this paper we demonstrate why the analogous characterizations fail to hold for higher-rank graphs (where one considers product systems of C*-correspondences) and for topological graphs (where V is locally compact Hausdorff), and we discuss the obstructions that arise.Comment: major revision; stated some results in greater generalit